Autosomal dominant polycystic kidney disease (ADPKD) is an exceptionally common inherited disorder in humans, affecting approximately one in every 600 to 1000 individuals (Gabow P. A., N Engl J Med 329(5):332-342, 1993). The disease is characterized by age dependent growth of renal cysts such that end-stage renal disease (ESRD) typically ensues during mid-adulthood. ADPKD may alternatively, or in addition, involve cysts in other organs including liver and spleen, as well as gastrointestinal, cardiovascular, and musculoskeletal abnormalities (Gabow P. A., N Engl J Med 329(5):332-342, 1993; Gabow P et al., Adv Nephrol 18:19-32, 1989). Both ADPKD type 1 and type 2 share the entire range of renal and extrarenal manifestations, but type 2 appears to have a delayed onset relative to type 1. The common phenotypic complications observed for ADPKD which include hypertension, hematuria and urinary tract infection, seem to be clinically milder in type 2 patients.
Approximately 85 percent of ADPKD cases are caused by mutations in the PKD1 gene [MIM 601313], which is located on chromosome 16, while the remainder are due to mutations in the PKD2 gene [MIM 173910] located on chromosome 4 (Peters et al., Contrib Nephrol 97:128-139, 1992; European Polycystic Kidney Disease Consortium, Cell, 77(6):881-894, 1994; International Polycystic Kidney Disease Consortium, Cell 81(2):289-298, 1995; Hughes J. et al, Nat Genet 10(2):151-160, 1995; Mochizuki T. et al., Science 272(5266):1339-1342, 1996). However, genetic testing for ADPKD has posed a unique set of challenges in terms of DNA diagnostics. PKD1 analysis in particular has been complicated because the 5′ portion of the gene (exons 1-34) is replicated in at least five highly homologous copies (with less than 2% divergence) elsewhere on chromosome 16 (Hughes J. et al, Nat Genet 10(2):151-160, 1995). Further complicating PKD1 mutant analysis, PKD1 has a high rate of potentially non-pathogenic DNA variation; thus the nature of each change detected must be verified. Several techniques have been used to detect mutations in the PKD1 gene including using gene-specific primers to amplify large products screened via nested PCR techniques, denaturing high-performance liquid chromatography (DHPLC) to screen nested PCR products for mutations and direct sequencing of the entire PKD1 coding sequence (Watnick T J et al., Hum Mol Genet 6(9):1473-1481, 1997; Watnick T J et al., Mol Cell 2(2):247-251, 1998; Watnick T. et al., Am J Hum Genet 65(6):1561-1571, 1999; Phakdeekitcharoen B. et al., Kidney Int 58(4):1400-1412, 2000; Phakdeekitcharoen B. et al., J Am Soc Nephrol 12:955-963, 2001; Thomas R. et al., Am J Hum Genet 65(1):39-49, 1999; Perichot R. A., Hum Genet 105(3):231-239, 1999; Perichot R. et al., Eur J Hum Genet 8(5):353-359, 2000; Afzal A. R. et al., Genet 4(4):365-370; Rossetti S. et al., Lancet 361(9376):2196-2201, 2003; Rossetti S. et al., Kidney Int 61:1588-1599, 2002; Rossetti S. et al., Am J Hum Genet 68(1):46-63, 2001, Inoue S. et al., Hum Mutat 19(6):622-628, 2002; Burtey S. et al., J Med Genet 39(6):422-429, 2002; Mizoguchi M. et al., J Hum Genet 46(9):511-517, 2001; Zhang D. Y. et al., Zhonghua Yi Xue Yi Chuan Xue Za Zhi 21(3):211-214, 2004). However, some of these strategies may not be cost effective for routine clinical sample analysis and/or their mutation detection rate has not been established or is inadequate. For example, direct DNA sequencing of the entire coding regions of PKD1 and PKD2 is considered necessary because no mutational hot spots have been identified in either PKD1 or PKD2. Although several pathogenic mutations in PKD1 and PKD2 have been identified, the known mutations do not account for all those individuals with ADPKD. Thus, to accurately diagnose and treat the disease, there remains a need to identify other mutations of PKD1 or PKD2 which are linked to ADPKD.